Alnylam Pharmaceuticals, Inc. announced that the HELIOS-A Phase 3 study of vutrisiran, an investigational RNAi therapeutic in development for the treatment of transthyretin-mediated (ATTR) amyloidosis, met all secondary endpoints measured at 18 months in patients with hATTR amyloidosis with polyneuropathy, including statistically significant improvements in neuropathy impairment, quality of life (QoL), gait speed, nutritional status and overall disability, relative to placebo, and non-inferiority of serum TTR reduction relative to the within-study patisiran arm. In HELIOS-A, patients treated with vutrisiran also showed improvement in exploratory cardiac endpoints including NT-proBNP and echocardiographic parameters relative to placebo, as well as technetium uptake, relative to baseline, in a planned cohort of patients. Vutrisiran also continued to demonstrate an encouraging safety and tolerability profile consistent with the previously reported Month 9 results.

Alnylam previously announced that HELIOS-A met its primary and secondary endpoints at 9 months and study results were presented at the 2021 American Academy of Neurology (AAN) Virtual Annual Meeting. HELIOS-A 18-Month Study Results. At 18 months, vutrisiran met all secondary endpoints in HELIOS-A, demonstrating statistically significant improvement in clinical endpoints compared to placebo and non-inferiority in serum TTR reduction compared to the within-study patisiran arm, specifically: Vutrisiran treatment (N=122) resulted in a 0.46 point mean decrease (improvement) in the modified Neuropathy Impairment Score (mNIS+7) from baseline at 18 months as compared to a 28.09 point mean increase (worsening) reported for the external placebo group (N=77), resulting in a 28.55 point mean difference relative to placebo (p equal to 6.5x10-20).

Vutrisiran treatment also resulted in an mNIS+7 improvement relative to baseline at 18 months in 48% of patients, compared with 4% of patients who received placebo.· Vutrisiran treatment resulted in a 1.2 point mean decrease (improvement) in Norfolk QoL-DN score from baseline at 18 months as compared to a 19.8 point mean increase (worsening) reported for the external placebo group, resulting in a mean 21.0 point difference relative to placebo (p equal to 1.8x10-10). 50% of patients treated with vutrisiran experienced improvement in quality of life relative to baseline at 18 months, compared with 10% of patients who received placebo. Vutrisiran achieved statistically significant improvement in gait speed (10-MWT), nutritional status (mBMI), and disability (R-ODS) at 18 months, compared with the external placebo group.

Vutrisiran treatment resulted in a 0.024 meters/second mean decrease in 10-MWT from baseline at 18 months as compared to a 0.264 meters/second mean decrease in the external placebo group, resulting in a mean 0.239 meters/second increase relative to placebo (p equal to 1.2x10-7). Vutrisiran treatment resulted in a 25.0 point mean increase (improvement) in mBMI from baseline at 18 months as compared to a 115.7 point mean decrease in the external placebo group, resulting in a 140.7 point mean increase relative to placebo (p equal to 4.2x10-15). Vutrisiran treatment resulted in a mean decrease of 1.5 points from baseline in R-ODS at 18 months as compared to a 9.9 point mean decrease in the external placebo group, resulting in an 8.4 point mean increase relative to placebo (p equal to 3.5x10-15).

As expected, non-inferiority of vutrisiran serum TTR reduction, relative to the within-study patisiran reference comparator, was established. Vutrisiran achieved a rapid and sustained reduction of serum TTR at 18 months, with a mean reduction from baseline of 88%. Patients treated with vutrisiran also showed the potential for improvement across exploratory cardiac endpoints.

Compared to placebo, patients in the vutrisiran arm demonstrated improvement in NT-proBNP, a biomarker of cardiac stress, with an adjusted geometric fold change in the vutrisiran patients of 0.94 and a change in placebo patients of 1.96 for a nominal p-value of 9.6x10-10. Patients treated with vutrisiran also demonstrated a trend towards improvement (nominal p values) in echocardiographic parameters, relative to placebo including cardiac output (p=1.144 x10-5), LV end diastolic volume (p=4.021 x10-5), Global longitudinal strain (p=0.3182) and mean LV wall thickness (p=0.5228). In a planned cohort, vutrisiran also reduced cardiac uptake of technetium on scintigraphy imaging, relative to baseline, providing potential evidence of reduced amyloid burden in the heart.

68% of patients improved in technetium uptake as assessed by normalized left ventricular total uptake and 65% of patients demonstrated improvement in assessment of heart to contralateral lung ratio. Furthermore, 28% showed a one grade or greater improvement in the Perugini grading scale, with 68% of patients maintaining a stable Perugini grade at Month 18, relative to baseline. Vutrisiran demonstrated an encouraging safety profile in HELIOS-A at 18 months.

There were three study discontinuations (2.5%) due to adverse events in the vutrisiran arm by Month 18, one due to a non-fatal event of heart failure and two due to deaths, neither of which was considered related to the study drug. During the 18-month treatment period there were two serious adverse events (SAEs) deemed related to vutrisiran by the study investigator, consisting of dyslipidemia and urinary tract infection. The two deaths and the two related SAEs were previously reported at Month 9. Treatment emergent adverse events (AEs) occurring in 10% or more patients included fall, pain in extremity, diarrhea, peripheral edema, urinary tract infection, arthralgia and dizziness; with the exception of pain in extremity and arthralgia, each of these events occurred at a similar or lower rate as compared with external placebo.

Injection site reactions (ISRs) were reported in five patients (4.1%) and were all mild and transient. There were no clinically significant changes in liver function tests (LFTs).